Florfenicol is a broad spectrum antibiotic with activity against many gram-negative and gram-positive bacteria. Florfenicol is useful for the prevention and treatment of bacterial infections due to susceptible pathogens in birds, reptiles, fish, shellfish and mammals. One of its primary uses is in the treatment of pneumonia and associated respiratory infections in cattle (often referred to generically as Bovine Respiratory Disease or BRD) caused by Mannhemia haemolytica, Pasturella multocida and(or) Haemophilus somnus. It is also indicated in the treatment of pododermatitis in cattle caused by Fusobacterium necrophorum and Bacterioides melaninogenicus, swine respiratory disease caused by Pasteurella multocida, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis and(or) Mycoplasma spp., colibacillosis in chickens caused by Escherichia coli, enteric septicemia in catfish caused by Edwardsiella ictaluri, and furunculosis in salmon caused by Aeromonas salmonicida. Other genera of bacteria that have exhibited susceptibility to florfenicol include. Enterobacter, Klebsiella, Staphylococcus, Enterococcus, Bordetella, Proteus, and Shigella. In particular, chloramphenicol resistant strains of organisms such as K. pneumoniae, E. cloacae, S. typhus and E. coli are susceptible to florfenicol.
Florfenicol is a structural analog of thiamphenicol, which in turn is a derivative of chloramphenicol in which the aromatic nitro group, which nitro group has been implicated in chloramphenicol-induced, non-dose related irreversible aplastic anemia in humans, is replaced with a methylsulfonyl group. Florfenicol has a fluorine atom in place of the primary hydroxyl group of chloramphenicol and thiamphenicol. This renders florfenicol less susceptible to deactivation by bacteria containing the plasmid-encoded enzyme, chloramphenicol acetyl transferase (CAT), which acetylates the primary hydroxyl group of chloramphenicol and thiamphenicol, thereby preventing them from binding to ribosomal subunits of susceptible bacteria. Ribosomal binding is the primary mechanism of action of the chloramphenicol antibiotics and results in inhibition of peptidyl transferase, which is responsible for the transfer of amino acids to growing peptide chains and subsequent protein formation in bacteria. Nonetheless, compounds having the primary hydroxyl group do have utility in the treatment of bacterial infections, as evidenced by the continuing use of chloramphenicol and thiampheniol throughout the world.
In recent years, a number of bacterial genera and species have begun to exhibit some resistance to florfenicol. For example, resistance has been observed in Salmonella species (Bolton, L. F., et al., Clin. Microbiol. 1999, 37, 1348), E. coli (Keyes, K., et al., Antimicrob. Agents Chemother., 2000, 44, 421.), Klebsiella pneumoniae (Cloeckaert, A., et al., Antimicrob. Agents Chemother., 2001, 45, 2381), and in the aquacultural pathogen, Photobacterium damselae subsp. piscicida (formerly Pasteurella piscicida) (Kim, E., et al., Microbiol. Immunol., 1996, 40, 665). This resistance has been traced to a highly conserved gene (flo) that produces an antibiotic efflux pump (Flo).
The emergence, and threatened spread, of resistance to florfenicol has fostered the need for new antibiotics that retain or exceed the activity of florfenicol, maintain its imperviousness to the CAT enzyme and, in addition, are not substrates for the Flo efflux pump. The compounds of the present invention are such antibiotics.